Abstract
Considering the fact that melatonin acts as protective agent in various cognitive impairment, we decided to explore the precise effect of pretreatment with melatonin on cognitive function, mitochondrial activity, apoptosis and synaptic integrity in aged rats anesthetized by propofol. We first randomly allocated the thirty Sprague Dawley rats into three groups: Control vehicle-treated group (Con), Propofol-treated group (Pro) and Melatonin + Propofol group (Mel + Pro). The Barnes maze, open field and contextual fear conditioning test were employed to evaluate spatial memory, exploratory behavior and general locomotor activity, and hippocampus-dependent learning and memory ability, respectively. Moreover, mitochondrial function (including reactive oxygen species, mitochondrial membrane potential and ATP levels) and apoptosis were detected in the regions of hippocampus (HIP) and prefrontal cortex (PFC). The results of behavioral tests suggested that melatonin improved propofol-induced memory impairment in aged rats. Melatonin mitigated mitochondrial dysfunction and decreased the apoptotic cell counts in the regions of HIP and PFC. Furthermore, prophylactic melatonin treatment also reversed the propofol-induced inactivation of PKA/CREB/BDNF signaling and synaptic dysfunction. On the whole, our results indicated that melatonin ameliorated the propofol-induced cognitive disorders via attenuating mitochondrial dysfunction, apoptosis, inactivation of PKA/CREB/BDNF signaling and synaptic dysfunction.
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All data and models generated or used during the study appear in the submitted article.
References:
Ali T, Badshah H, Kim TH, Kim MO (2015) Melatonin attenuates D-galactose-induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF-K B/JNK signaling pathway in aging mouse model. J Pineal Res 58:71–85. https://doi.org/10.1111/jpi.12194
Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5:11708. https://doi.org/10.1038/srep11708
Alirezaei M, Rezaei M, Hajighahramani S, Sookhtehzari A, Kiani K (2017) Oleuropein attenuates cognitive dysfunction and oxidative stress induced by some anesthetic drugs in the hippocampal area of rats. J Physiol Sci 67:131–139. https://doi.org/10.1007/s12576-016-0446-3
Amin FU, Shah SA, Kim MO (2016) Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain. Neurochem Int 96:1–12. https://doi.org/10.1016/j.neuint.2016.04.001
Areti, A., Komirishetty, P., Akuthota, M., Malik, R.A., and Kumar, A. (2017). Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res 62. 10.1111/jpi.12393
Chang CC, Huang TY, Chen HY, Huang TC, Lin LC et al (2018) Protective effect of melatonin against oxidative Stress-Induced apoptosis and enhanced autophagy in human retinal pigment epithelium cells. Oxid Med Cell Longev 2018:9015765. https://doi.org/10.1155/2018/9015765
Chern CM, Liao JF, Wang YH, Shen YC (2012) Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice. Free Radic Biol Med 52:1634–1647. https://doi.org/10.1016/j.freeradbiomed.2012.01.030
Cuesta S, Kireev R, Garcia C, Forman K, Escames G et al (2011) Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model. Mech Ageing Dev 132:573–582. https://doi.org/10.1016/j.mad.2011.10.005
Dai C, Ciccotosto GD, Cappai R, Wang Y, Tang S et al (2018) Rapamycin confers neuroprotection against Colistin-Induced oxidative stress, mitochondria dysfunction, and apoptosis through the activation of autophagy and mTOR/Akt/CREB signaling pathways. ACS Chem Neurosci 9:824–837. https://doi.org/10.1021/acschemneuro.7b00323
Deng X, Chen B, Wang B, Zhang J, Liu H (2017) TNF-alpha mediates the intrinsic and extrinsic pathway in Propofol-Induced neuronal apoptosis via PI3K/Akt signaling pathway in rat prefrontal cortical neurons. Neurotox Res 32:409–419. https://doi.org/10.1007/s12640-017-9751-8
Ding ML, Ma H, Man YG, Lv HY (2017) Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol 95:1396–1405. https://doi.org/10.1139/cjpp-2016-0333
Finsterer J, Frank M (2016) Propofol is Mitochondrion-Toxic and may unmask a mitochondrial disorder. J Child Neurol 31:1489–1494. https://doi.org/10.1177/0883073816661458
Goel R, Bhat SA, Hanif K, Nath C, Shukla R (2018) Angiotensin II receptor blockers attenuate Lipopolysaccharide-Induced memory impairment by modulation of NF-kappaB-Mediated BDNF/CREB expression and apoptosis in spontaneously hypertensive rats. Mol Neurobiol 55:1725–1739. https://doi.org/10.1007/s12035-017-0450-5
Grundmanova M, Jarkovska D, Suss A, Tuma Z, Markova M et al (2016) Propofol-induced mitochondrial and contractile dysfunction of the rat ventricular myocardium. Physiol Res 65:S601–S609
Guan R, Lv J, Xiao F, Tu Y, Xie Y et al (2019) Potential role of the cAMP/PKA/CREB signalling pathway in hypoxic preconditioning and effect on propofolinduced neurotoxicity in the hippocampus of neonatal rats. Mol Med Rep 20:1837–1845. https://doi.org/10.3892/mmr.2019.10397
Hoppe JB, Frozza RL, Horn AP, Comiran RA, Bernardi A et al (2010) Amyloid-beta neurotoxicity in organotypic culture is attenuated by melatonin: Involvement of GSK-3beta, tau and neuroinflammation. J Pineal Res 48:230–238. https://doi.org/10.1111/j.1600-079X.2010.00747.x
Jiang LL, Zhang FP, He YF, Fan WG, Zheng MM et al (2019) Melatonin regulates mitochondrial function and biogenesis during rat dental papilla cell differentiation. Eur Rev Med Pharmacol Sci 23:5967–5979. https://doi.org/10.26355/eurrev_201907_18343
Kahraman S, Zup SL, McCarthy MM, Fiskum G (2008) GABAergic mechanism of propofol toxicity in immature neurons. J Neurosurg Anesthesiol 20:233–240. https://doi.org/10.1097/ANA.0b013e31817ec34d
Kapoor I, Prabhakar H, Mahajan C (2019) Postoperative cognitive dysfunction. Indian J Crit Care Med 23:S162–S164. https://doi.org/10.5005/jp-journals-10071-23196
Letechipia-Vallejo G, Lopez-Loeza E, Espinoza-Gonzalez V, Gonzalez-Burgos I, Olvera-Cortes ME et al (2007) Long-term morphological and functional evaluation of the neuroprotective effects of post-ischemic treatment with melatonin in rats. J Pineal Res 42:138–146. https://doi.org/10.1111/j.1600-079X.2006.00395.x
Li H, Yu F, Sun X, Xu L, Miu J et al (2019) Dihydromyricetin ameliorates memory impairment induced by acute sleep deprivation. Eur J Pharmacol 853:220–228. https://doi.org/10.1016/j.ejphar.2019.03.014
Li J, Guo M, Liu Y, Wu G, Miao L et al (2019) Both GSK-3beta/CRMP2 and CDK5/CRMP2 pathways participate in the protection of dexmedetomidine against propofol-induced learning and memory impairment in neonatal rats. Toxicol Sci. https://doi.org/10.1093/toxsci/kfz135
Li, J., Li, D., Zhou, H., Wu, G., and He, Z., et al. (2020). MicroRNA-338-5p alleviates neuronal apoptosis via directly targeting BCL2L11 in APP/PS1 mice. Aging (Albany NY) 12. 10.18632/aging.104005
Lin MC, Lin CF, Li CF, Sun DP, Wang LY et al (2015) Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production. Int J Mol Sci 16:12092–12107. https://doi.org/10.3390/ijms160612092
Luo T, Wu J, Kabadi SV, Sabirzhanov B, Guanciale K et al (2013) Propofol limits microglial activation after experimental brain trauma through inhibition of nicotinamide adenine dinucleotide phosphate oxidase. Anesthesiology 119:1370–1388. https://doi.org/10.1097/ALN.0000000000000020
Maldonado MD, Murillo-Cabezas F, Terron MP, Flores LJ, Tan DX et al (2007) The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma. J Pineal Res 42:1–11. https://doi.org/10.1111/j.1600-079X.2006.00376.x
Netto MB, de Oliveira JA, Goldim M, Mathias K, Fileti ME et al (2018) Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats. Brain Behav Immun 73:661–669. https://doi.org/10.1016/j.bbi.2018.07.016
Petrosillo G, Fattoretti P, Matera M, Ruggiero FM, Bertoni-Freddari C et al (2008) Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res 11:935–943. https://doi.org/10.1089/rej.2008.0772
Qi G, Mi Y, Wang Y, Li R, Huang S et al (2017) Neuroprotective action of tea polyphenols on oxidative stress-induced apoptosis through the activation of the TrkB/CREB/BDNF pathway and Keap1/Nrf2 signaling pathway in SH-SY5Y cells and mice brain. Food Funct 8:4421–4432. https://doi.org/10.1039/c7fo00991g
Rehman, S.U., Ikram, M., Ullah, N., Alam, S.I., and Park, H.Y., et al. (2019). Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK/CREB Signaling. Cells 8. 10.3390/cells8070760
Rodriguez MI, Escames G, Lopez LC, Lopez A, Garcia JA et al (2008) Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice. Exp Gerontol 43:749–756. https://doi.org/10.1016/j.exger.2008.04.003
Salehpour F, Ahmadian N, Rasta SH, Farhoudi M, Karimi P et al (2017) Transcranial low-level laser therapy improves brain mitochondrial function and cognitive impairment in D-galactose-induced aging mice. Neurobiol Aging 58:140–150. https://doi.org/10.1016/j.neurobiolaging.2017.06.025
Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A et al (2011) General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 115:992–1002. https://doi.org/10.1097/ALN.0b013e3182303a63
Sharif R, Aghsami M, Gharghabi M, Sanati M, Khorshidahmad T et al (2017) Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function. Behav Brain Res 316:115–124. https://doi.org/10.1016/j.bbr.2016.08.040
Shen, Y.Q., Guerra-Librero, A., Fernandez-Gil, B.I., Florido, J., and Garcia-Lopez, S., et al. (2018). Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. J Pineal Res 64. 10.1111/jpi.12461
Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2018) Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Exp Gerontol 101:13–36. https://doi.org/10.1016/j.exger.2017.10.029
Sumi C, Okamoto A, Tanaka H, Nishi K, Kusunoki M et al (2018) Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. PLoS ONE 13:e192796. https://doi.org/10.1371/journal.pone.0192796
Tang Y, Cai B, Yuan F, He X, Lin X et al (2014) Melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia. Cell Transplant 23:1279–1291. https://doi.org/10.3727/096368913x667510
Verret L, Trouche S, Zerwas M, Rampon C (2007) Hippocampal neurogenesis during normal and pathological aging. Psychoneuroendocrinology 32(Suppl 1):S26–S30. https://doi.org/10.1016/j.psyneuen.2007.04.014
Wang S, Feng D, Li Y, Wang Y, Sun X et al (2018) The different baseline characteristics of cognitive behavior test between Mongolian gerbils and rats. Behav Brain Res 352:28–34. https://doi.org/10.1016/j.bbr.2017.09.042
Wang Y, Yu T, Yuan C, Yuan J, Luo Z et al (2016) Effects of propofol on the dopamine, metabolites and GABAA receptors in media prefrontal cortex in freely moving rats. Am J Transl Res 8:2301–2308
Wang YL, Chen X, Wang ZP (2015) Detrimental effects of postnatal exposure to propofol on memory and hippocampal LTP in mice. Brain Res 1622:321–327. https://doi.org/10.1016/j.brainres.2015.06.044
Wen J, Ariyannur PS, Ribeiro R, Tanaka M, Moffett JR et al (2016) Efficacy of N-Acetylserotonin and melatonin in the EAE model of multiple sclerosis. J Neuroimmune Pharmacol 11:763–773. https://doi.org/10.1007/s11481-016-9702-9
Wu H, Shao A, Zhao M, Chen S, Yu J et al (2016) Melatonin attenuates neuronal apoptosis through up-regulation of K(+) -Cl(-) cotransporter KCC2 expression following traumatic brain injury in rats. J Pineal Res 61:241–250. https://doi.org/10.1111/jpi.12344
Xiong M, Li J, Alhashem HM, Tilak V, Patel A et al (2014) Propofol exposure in pregnant rats induces neurotoxicity and persistent learning deficit in the offspring. Brain Sci 4:356–375. https://doi.org/10.3390/brainsci4020356
Yang N, Li L, Li Z, Ni C, Cao Y et al (2017) Protective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy. Neurosci Lett 649:85–92. https://doi.org/10.1016/j.neulet.2017.04.019
Yang Y, Jiang S, Dong Y, Fan C, Zhao L et al (2015) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 58:61–70. https://doi.org/10.1111/jpi.12193
Zhang HM, Zhang Y (2014) Melatonin: A well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57:131–146. https://doi.org/10.1111/jpi.12162
Zhang X, Dong H, Li N, Zhang S, Sun J et al (2016) Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis. J Neuroinflammation 13:127. https://doi.org/10.1186/s12974-016-0592-9
Zheng HB, Fu YT, Wang G, Sun LH, Fan YY et al (2018) Hyperphosphorylation of protein Tau in hippocampus may cause cognitive dysfunction of propofol-anesthetized rats. Eur Rev Med Pharmacol Sci 22:3577–3585. https://doi.org/10.26355/eurrev_201806_15184
Zhong Y, Chen J, Li L, Qin Y, Wei Y et al (2018) PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats. Brain Res 1691:64–74. https://doi.org/10.1016/j.brainres.2018.04.022
Funding
This work was supported by the Natural Science Foundation of Guangdong Province, China (No.2016A030313251, No.2018A0303130272, No.2016A030313827); the Science and Technology Planning Project of Guangzhou, China (No. 201707010207).
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Junhua Li, Guiyun Wu: Investigation, Methodology, Writing-Original draft preparation. Wen Song and Yafang Liu: Conceptualization, Data curation. Zhixiao Han: Visualization, Software, Supervision. Zhiwen Shen and Yujuan Li: Writing-Reviewing and Editing.
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Significance Statement
The present study suggests that melatonin improves the memory impairment induced by propofol and confirms that this neuroprotective effect is associated with its antioxidant and antiapoptotic properties. The neuroprotective mechanisms of melatonin may involve restoring the inactivation of PKA/CREB/BDNF signaling and synaptic dysfunction caused by propofol.
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12640_2020_307_MOESM1_ESM.tif
Supplementary file1: Figure. S1 Overactivation of PKA/CREB/BDNF signaling ameliorated the propofol-induced synaptic dysfunction. (A) Relative mRNA level of PKA, p-CREB and BDNF tested by qRT-PCR. (B) Representative Western blot of Syntaxin and PSD95 in hippocampus and prefrontal cortex regions. (C-D) The quantitative analysis of the ratio of Syntaxin/β-actin (C) and PSD95/β-actin (D) in hippocampus region. (E–F) The quantitative analysis of the ratio of Syntaxin/β-actin (E) and PSD95/β-actin (F) in prefrontal cortex region. Significant differences were tested by one-way ANOVA followed by Tukey’s post hoc test. Data are expressed as the mean ± S.E.M. (n = 3). Con: Control group, Pro: Propofol group, Sp-cAMP + Pro: Sp-cAMP + Propofol group. *P < 0.05,**P < 0.01, ***P < 0.001 versus Con. #P < 0.05, ##P < 0.01 versus Pro: (TIF 515 kb)
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Li, J., Wu, G., Song, W. et al. Prophylactic Melatonin Treatment Ameliorated Propofol-Induced Cognitive Dysfunction in Aged Rats. Neurotox Res 39, 227–239 (2021). https://doi.org/10.1007/s12640-020-00307-9
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DOI: https://doi.org/10.1007/s12640-020-00307-9